Abstract Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 136,000 new cases and 50,000 deaths are predicted for the year 2017; this mortality is predominantly due to the development of disseminated advanced disease. A better understanding of the metastatic tumor and its microenvironment is urgently needed in order to improve the overall survival of colorectal cancer patients. My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases, PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase), in inhibiting colon cancer initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. The main goal of the parent R01 grant is to determine the effect of PHLPP-loss on modulating colon cancer metabolism. We have been highly productive in the past 4 years with 15 total publications. Recently, our efforts on examining PHLPP-mediated regulation of cellular metabolism in colon cancer have led to exciting new findings and opened up new collaboration opportunities. Locally advanced tumor cells often invade into surrounding adipose tissue with a direct contact with adipocytes. However, how adipocytes support tumor growth and progression is poorly understood. We discovered a direct metabolic crosstalk between colon cancer cells and adipocytes in the tumor microenvironment. The overall objective of studies proposed here is to develop a mechanistic understanding of adipocytes-mediated tumor promoting effects in colon cancer. The central hypothesis driving this proposal is that colon cancer cells grown in the presence of adipocytes in the tumor microenvironment will adapt a distinct metabolic program that enhance cancer stem cell-like properties by upregulating mitochondrial fatty acid oxidation (FAO). Specifically, we will further delineate the role of mitochondrial FAO in mediating the tumor promoting effect of adipocytes and determine how adipocyte-induced activation of FAO regulates cancer stem cell properties both in vitro and in vivo. To ensure the success of this study, I have established new collaboration with Dr. Daret St Clair, an expert in mitochondrial biology. This collaboration represents a natural extension of research interests of both laboratories. Through close interactions, we have built a strong investigative team that has the requisite expertise, innovative model systems and state-of-the-art technology to make rapid progress. Results from this study will provide novel insights into the molecular mechanism underlying the tumor-promoting effect of adipocytes in colon cancer. Furthermore, developing a mechanistic understanding of how mitochondrial FAO promotes cancer stem cell properties will help to identify new therapeutic interventions to target and eliminate cancer stem cells in order to prevent cancer relapse and improve treatment outcomes.